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Based on our previous finding of hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia\u2010inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non\u2010smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF\u20101\u03b1 nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 \u00b1 3.9% (range 65\u2013100%) of goblet cells were HIF\u20101\u03b1 positive in areas of goblet cell hyperplasia, whereas nuclear HIF\u20101\u03b1 was not detected in individuals without COPD or in normal\u2010appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia\u2010inducible signalling on epithelial cell differentiation <jats:italic>in vitro<\/jats:italic>, human bronchial epithelial cells (HBECs) were grown in air\u2013liquid interface cultures under hypoxia (1% O<jats:sub>2<\/jats:sub>) or following treatment with a selective HIF\u20101\u03b1 stabilizer, (2<jats:italic>R<\/jats:italic>)\u2010[(4\u2010biphenylylsulphonyl)amino]\u2010<jats:italic>N<\/jats:italic>\u2010hydroxy\u20103\u2010phenyl\u2010propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF\u20101\u03b1 activation, carbonic anhydrase IX expression, mucus\u2010producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF\u20101\u03b1 activation showed increased ERK1\/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K\u2010Akt or STAT6. These data indicate an important effect of hypoxia\u2010inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2863","type":"journal-article","created":{"date-parts":[[2011,2,3]],"date-time":"2011-02-03T09:14:31Z","timestamp":1296724471000},"page":"203-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Hypoxia\u2010inducible factor\u20101 signalling promotes goblet cell hyperplasia in airway epithelium"],"prefix":"10.1002","volume":"224","author":[{"given":"Vasiliy V","family":"Polosukhin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M","family":"Cates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E","family":"Lawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron 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